Analogs of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) will be prepared and enzymatically evaluated in an attempt to elucidate the structural requirements at the active site of various SAM-dependent methyl-transferases. The enzymes of particular interest will be catechol-O-methyl-transferase (COMT), phenethanolimine-N-methyltransferase (PNMT), histamine-N-methyltransferase (HNMT) and hydroxyindole-O-methyltransferase (HIOMT), which are all important in the biosynthesis and/or metabolism of biogenic amines. Also of interest will be homocysteine-S-methyltransferase (HSMT), which is important in the biosynthesis of methionine and t-RNA methylase, which is responsible for the methylation of t-RNA. The structural modifications of SAM and SAH will involve primarily changes in the adenine moiety. These changes will include replacement of the adenine moiety by various 6-substituted 1-deazapurines, 3-deazapurines, 7-deazapurines, 2-azapurines and 8-azapurines, as well as replacement by 5-aminoimidazole-4-carboxamidoxime and 5-amino-imidaxole-4-carboxamidine. Also of interest will be various sugar modified analogs of SAM or SAH. Of primary interest will be modifications of the 2'- and 3' -hydroxyl groups. Evaluation of the SAM analogs as potential substrates or inhibitors, and the SAH analogs as potential inhibitors for these enzymes will permit a more detailed delineation of the similarities of differences in the active sites of these enzymes. Observed differences in active sites of these enzymes and their specificity toward SAM or SAH analogs will hopefully lead to the design of specific inhibitors for one or more of these enzymes. Of particular interest will be the inhibition of COMT, because of the usefulness of such inhibitors to potentiate the CNS effects of L-DOPA in the treatment of Parkinsons disease. BIBLIOGRAPHIC REFERENCES: R. T. Borchardt and Y. S. Wu, "Potential Inhibitors of S-Adenosyl-methionine-Dependent Methyltransferases. III. Modifications of the Sugar Portion of S-Adenosylmethionine", J. Med. Chem., 18, 300 (1975). R. T. Borchardt, C. F. Cheng and D. R. Thakker, "Purification of Catechol-0-Methyltransferase by Affinity Chromatography", Biochem. Biophys. Res. Commun., 63, 69 (1975).